Tumor- and host-derived heparanase-2 (Hpa2) attenuates tumorigenicity: role of Hpa2 in macrophage polarization and BRD7 nuclear localization DOI Creative Commons

Soaad Soboh,

Avital Vorontsova,

Malik Farhoud

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(12)

Published: Dec. 18, 2024

Abstract Little attention was given to heparanase 2 (Hpa2) over the last two decades, possibly because it lacks a heparan sulfate (HS)-degrading activity typical of heparanase. Emerging results suggest, nonetheless, that Hpa2 plays role in human pathologies, including cancer progression where functions as tumor suppressor. Here, we examined cervical carcinoma. We report high levels correlate with prolonged survival carcinoma patients. Strong staining intensity also correlates low grade. Overexpression SiHa cells resulted xenografts were two-fold smaller than control tumors. Interestingly, even developed by overexpressing Pro140Arg and Asn543Ile missense mutations identified patients diagnosed urofacial syndrome (UFS). Utilizing Ras recruitment system, bromodomain-containing protein 7 (BRD7) interact found both BRD7 mutants are translocated cell nucleus tumors mutants. our newly conditional Hpa2-KO mice, further show critical macrophage polarization; absence Hpa2, macrophages shifted towards pro-tumorigenic, M2 phenotype. Notably, implanting together promoted growth. These support, expand, notion suppressor, co-operating another BRD7.

Language: Английский

Impact of heparanase‐2 (Hpa2) on cancer and inflammation: Advances and paradigms DOI Creative Commons
Israël Vlodavsky,

Maram Hilwi,

Yasmin Kayal

et al.

The FASEB Journal, Journal Year: 2024, Volume and Issue: 38(10)

Published: May 15, 2024

Abstract HPSE2 , the gene‐encoding heparanase 2 (Hpa2), is mutated in urofacial syndrome (UFS), a rare autosomal recessive congenital disease attributed to peripheral neuropathy. Hpa2 lacks intrinsic heparan sulfate (HS)‐degrading activity, hallmark of (Hpa1), yet it exhibits high affinity toward HS, thereby inhibiting Hpa1 enzymatic activity. regulates selected genes that promote normal differentiation, tissue homeostasis, and endoplasmic reticulum (ER) stress, resulting antitumor, antiangiogenic, anti‐inflammatory effects. Importantly, stress conditions induce expression Hpa2, thus establishing feedback loop, where enhances ER which, turn, induces expression. In most cases, cancer patients who retain levels survive longer than bearing Hpa2‐low tumors. Experimentally, overexpression attenuates growth tumor xenografts, whereas gene silencing results aggressive Studies applying conditional knockout (cHpa2‐KO) mice revealed an essential involvement contributed by host protecting against inflammation. This was best reflected distorted morphology Hpa2‐null pancreas, including massive infiltration immune cells, acinar adipocyte trans‐differentiation, ductal metaplasia. Moreover, orthotopic inoculation pancreatic adenocarcinoma (PDAC) cells into pancreas vs. wild‐type yielded tumors were far more aggressive. Likewise, intravenous cHpa2‐KO resulted dramatically increased lung colonization reflecting restricting formation premetastatic niche. Elucidating structure–activity‐relationships expected support development Hpa2‐based therapies

Language: Английский

Citations

6
Current understanding of heparanase 2 regulation, a non-heparanase DOI Creative Commons

Yannic Becker,

Hermann Haller

Biochemical Society Transactions, Journal Year: 2025, Volume and Issue: 53(01)

Published: Feb. 5, 2025

Language: Английский

Citations

0
Unveiling epigenetic regulatory elements associated with breast cancer development DOI Creative Commons
Marta Jardanowska, Michał Dramiński, Michał Wlasnowolski

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Breast cancer is the most common in women and 2nd worldwide, yearly impacting over 2 million females causing 650 thousand deaths. It has been widely studied, but its epigenetic variation not entirely unveiled. We aimed to identify mechanisms expression of breast related genes detect new potential biomarkers therapeutic targets. considered The Cancer Genome Atlas database with 800 samples several omics datasets such as mRNA, miRNA, DNA methylation, which we used select 2701 features that were statistically significant differ between control using Monte Carlo Feature Selection Interdependency Discovery algorithm, from an initial total 417,486. Their biological impact on cancerogenesis was confirmed using: statistical analysis, natural language processing, linear machine learning models well as: transcription factors identification, drugs 3D chromatin structure analyses. Classification vs selected returned high classification weighted Accuracy 0.91 0.98 depending feature-type: algorithm. In general, showed lower differentially expressed increased

Language: Английский

Citations

0
Tumor- and host-derived heparanase-2 (Hpa2) attenuates tumorigenicity: role of Hpa2 in macrophage polarization and BRD7 nuclear localization DOI Creative Commons

Soaad Soboh,

Avital Vorontsova,

Malik Farhoud

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(12)

Published: Dec. 18, 2024

Abstract Little attention was given to heparanase 2 (Hpa2) over the last two decades, possibly because it lacks a heparan sulfate (HS)-degrading activity typical of heparanase. Emerging results suggest, nonetheless, that Hpa2 plays role in human pathologies, including cancer progression where functions as tumor suppressor. Here, we examined cervical carcinoma. We report high levels correlate with prolonged survival carcinoma patients. Strong staining intensity also correlates low grade. Overexpression SiHa cells resulted xenografts were two-fold smaller than control tumors. Interestingly, even developed by overexpressing Pro140Arg and Asn543Ile missense mutations identified patients diagnosed urofacial syndrome (UFS). Utilizing Ras recruitment system, bromodomain-containing protein 7 (BRD7) interact found both BRD7 mutants are translocated cell nucleus tumors mutants. our newly conditional Hpa2-KO mice, further show critical macrophage polarization; absence Hpa2, macrophages shifted towards pro-tumorigenic, M2 phenotype. Notably, implanting together promoted growth. These support, expand, notion suppressor, co-operating another BRD7.

Language: Английский

Citations

0